Annexin A7 and JNK knockdown suppress the lymphatic metastasis potential of hepatocellular carcinoma cells: Possible contributions of ATF2 and sequence-related lncRNA NONMMUT114121.1

BACKGROUND: Our previous studies identified the calcium-dependent phospholipid binding protein Annexin A7 (ANXA7) as a critical mediator of hepatocellular carcinoma (HCC) lymph node metastasis (LNM) in mice, possibly through c-Jun N-terminal kinase (JNK) signaling. Activating transcription factor-2 (ATF2) is a downstream target of JNK, so we examined if modulation of LNM capacity by ANXA7 and JNK is associated with changes in ATF2 activity and its sequence-related long non-coding (lnc)RNA NONMMUT114121.1. METHODS: The effects of shRNA-induced ANXA7 and JNK knockdown on HCC cell transwell invasion, HCC cell lymphatic tissue adherence, ATF2 mRNA and protein expression, and ATF2 subcellular distribution were examined in the murine HCC cell line Hca-P. RESULTS: Invasive capacity, lymphoid adhesion, and ATF2 expression at both mRNA and protein levels were significantly reduced by ANXA7 or JNK knockdown (all P<0.05). Immunofluorescence revealed that ATF2 was mainly localized to the nucleus of control Hca-P cells, but this nuclear expression was markedly reduced by ANXA7 or JNK knockdown. LncRNA NONMMUT114121.1 was associated with ATF2 by sequencing and its expression level was significantly increased by ANXA7 knockdown (P<0.05). CONCLUSIONS: JNK and ANXA7 promote the invasive capacity and lymphatic adherence of Hca-P cells, possibly through ATF2 activation and its related lncRNA NONMMUT114121.1. Nuclear ATF2 may thus be a potential diagnostic and/or prognostic biomarker for HCC.